We seek renewal of the core operating funding for the Reactome Knowledgebase of Human Biological Pathways and Processes. Reactome is a curated knowledgebase available online as an open access resource that can be freely used and redistributed by all members of the biological research community. It is used by geneticists, genomics researchers, clinical researchers and molecular biologists to interpret the results of high-throughput experimental studies, by bioinformaticians seeking to develop novel algorithms for mining knowledge from genomics studies, and by systems biologists building predictive models of normal and abnormal pathways. Our curational system draws heavily on the expertise of independent investigators within the community who author precise machine-readable descriptions of human biological pathways under the guidance of a staff of dedicated curators. Each pathway is extensively checked and peer-reviewed prior to publication to ensure its factual accuracy and compliance with the data model. A system of evidence tracking ensures that all assertions are backed up by the primary literature, and that human molecular events inferred from orthologous ones in animal models have an auditable inference chain. Curated pathways described by Reactome currently cover roughly one quarter of the translated portion of the genome. We also offer a network of functional interactions (FIs) predicted by a conservative machine-learning approach, that covers an additional quarter of the translated genome, for a combined coverage of roughly 50% of the known genome. Over the next five years, we seek to (1) increase the number of curated proteins and other functional entities to at least 10,500; (2) to supplement normal pathways with variant reactions for 1200 genes representing disease states; (3) increase the size of the Reactome Fl network to 15,000 molecules; and (4) enhance the web site and other resources to meet the needs of a growing and diverse user community. PUBLIC HEALTH RELEVANCE: RELEVANCE (See instructions): Reactome represents one of a very small number of fully open access curated pathway databases. Its contents have contributed both directly and indirectly to large numbers of basic and translational research studies, and it supports a broad, diverse and engaged user community. As such it represents a key and irreplaceable community resource for genomics, genetics, systems biology, and translational researchers.